NALP1 is a member of the NOD-like receptor (NLR) family of proteins that form inflammasomes. Upon cellular infection or stress, inflammasomes are activated, triggering maturation of proinflammatory cytokines and downstream cellular signaling mediated through the MyD88 adaptor. Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines that are important in innate immunity. In this study, susceptibility alleles for human congenital toxoplasmosis were identified in the NALP1 gene. To investigate the role of the NALP1 inflammasome during infection with T. gondii, we genetically engineered a human monocytic cell line for NALP1 gene knockdown by RNA interference. NALP1 silencing attenuated progression of T. gondii infection, with accelerated host cell death and eventual cell disintegration. In line with this observation, upregulation of the proinflammatory cytokines interleukin-1␤ (IL-1␤), IL-18, and IL-12 upon T. gondii infection was not observed in monocytic cells with NALP1 knockdown. These findings suggest that the NALP1 inflammasome is critical for mediating innate immune responses to T. gondii infection and pathogenesis. Although there have been recent advances in understanding the potent activity of inflammasomes in directing innate immune responses to disease, this is the first report, to our knowledge, on the crucial role of the NALP1 inflammasome in the pathogenesis of T. gondii infections in humans.

Toxoplasmosis is a healthcare problem in pregnant women and immunocompromised patients. Like humans, rats usually develop a subclinical chronic infection. LEW rats exhibit total resistance to Toxoplasma gondii infection, which is expressed in a dominant mode. A genome-wide search carried out in a cohort of F 2 progeny of susceptible BN and resistant LEW rats led to identify on chromosome 10 a major locus of control, which we called Toxo1. Using reciprocal BN and LEW lines congenic for chromosome 10 genomic regions from the other strain, Toxo1 was found to govern the issue of T. gondii infection whatever the remaining genome. Analyzes of rats characterized by genomic recombination within Toxo1, reduced the interval down to a 1.7-cM region syntenic to human 17p13. In vitro studies showed that the Toxo1-mediated refractoriness to T. gondii infection is associated with the ability of the macrophage to impede the proliferation of the parasite within the parasitophorous vacuole. In contrast, proliferation was observed in fibroblasts whatever the genomic origin of Toxo1. Furthermore, ex vivo studies indicate that macrophage controls parasitic infection spreading by a Toxo1-mediated mechanism. This forward genetics approach should ultimately unravel a major pathway of innate resistance to toxoplasmosis and possibly to other apicomplexan parasitic diseases.T he protozoan Toxoplasma gondii is an obligate intracellular parasite that infects humans and a broad spectrum of vertebrate hosts. It is found worldwide, and the infection is common as indicated by a high prevalence of specific Ab among almost all human populations. T. gondii infection occurs by oral ingestion of either cysts from infected animal tissues, or oocysts excreted by cats. In healthy individuals, T. gondii establishes a chronic asymptomatic infection characterized by a specific immune response and the encystment of dormant bradyzoites into host tissues. A serious threat to human health can occur under congenital infection or reactivation of a latent infection in immunodeficient patients (1).Epidemiological studies have indicated that the genetic make-up of the host and of the parasite are involved in the phenotypic expression of toxoplasmosis (2-4). Genetic studies in humans are hampered by both population heterogeneity and environment variability. In experimental conditions, genetic and environmental factors are under control. Results from genetic studies in animal models can be applied to human pathology through comparative genomics (5, 6). Rats, like humans, usually develop subclinical toxoplasmosis (7); this contrasts with the severity of the disease developed in most strains of mice. Surprisingly, the LEW rat strain exhibits a complete resistance to Toxoplasma infection (8). Indeed, unlike susceptible BN and F344 rats, LEW rats do not show trace of parasitic infection as shown by negative serology and lack of brain cysts. F 1 hybrid (LEW ϫ BN) and (LEW ϫ F344) rats are resistant to T. gondii, indicating a dominant effect of the involved gene(s) (9). W...